Jiangxi Institute for Drug Control, NMPA Key Laboratory of Quality Evaluation of Traditional Chinese Patent Medicine, Jiangxi Province Engineering Research Center of Drug and Medical Device Quality, Nanchang, 330029, China.
Jiangxi Institute for Drug Control, NMPA Key Laboratory of Quality Evaluation of Traditional Chinese Patent Medicine, Jiangxi Province Engineering Research Center of Drug and Medical Device Quality, Nanchang, 330029, China.
J Pharm Biomed Anal. 2021 Jan 30;193:113731. doi: 10.1016/j.jpba.2020.113731. Epub 2020 Nov 2.
Cloperastine hydrochloride, a piperidine derivative, is a drug substance with a central antitussive effect and widely used in cough treatment; and its impurities have not been reported. Herein we isolated and identified five impurities (named as impurity A, B, C, D and E) in cloperastine hydrochloride bulk drug and developed a quantitative HPLC method. First, impurity A, B, C were enriched by ODS column chromatography and isolated by semi-preparative HPLC, at the same time, impurity D was purified by ODS column chromatography. Then, impurity E was enriched by strong acid degradation and purified by semi-preparative HPLC. At last, their structures were characterized by a variety of spectral data (MS, H NMR, C NMR, HSQC, HMBC and H-H COSY). Impurity A was confirmed as 1-[2-(diphenylmethoxy)ethyl]piperidine, which having one less chloro-substituent compared with cloperastine. Impurity B was confirmed as 1-[2-[(2-chlorophenyl)(phenyl)methoxy]ethyl]piperidine, which was the isomer of cloperastine with 2-chloro-substituent. Impurity C was confirmed as 1-[2-[(3-chlorophenyl)(phenyl)methoxy]ethyl]piperidine, which was the isomer of cloperastine with 3-chloro-substituent. Impurity D was confirmed as (4-chlorophenyl)(phenyl)methanone, which was the raw material for the synthesis of cloperastine. Impurity E was confirmed as (4-chlorophenyl)(phenyl)methanol, which was an intermediate in the synthesis of cloperastine, and it was also a hydrolysate of cloperastine. Finally, the developed method was validated in terms of specificity, linearity, sensitivity, precision and accuracy.
氢氯酸咯培龙，一种哌啶衍生物，是一种具有中枢镇咳作用的药物物质，广泛用于咳嗽治疗；其杂质尚未有报道。在此，我们从盐酸咯培龙原料药中分离并鉴定了五种杂质（分别命名为杂质 A、B、C、D 和 E），并建立了一种定量 HPLC 方法。首先，通过 ODS 柱色谱法对杂质 A、B、C 进行富集，并通过半制备 HPLC 进行分离，同时通过 ODS 柱色谱法对杂质 D 进行纯化。然后，通过强酸降解对杂质 E 进行富集，并通过半制备 HPLC 进行纯化。最后，通过多种光谱数据（MS、H NMR、C NMR、HSQC、HMBC 和 H-H COSY）对其结构进行了表征。杂质 A 被确认为 1-[2-(二苯甲氧基)乙基]哌啶，与咯培龙相比，其少了一个氯取代基。杂质 B 被确认为 1-[2-[(2-氯苯基)(苯基)甲氧基]乙基]哌啶，是咯培龙的异构体，具有 2-氯取代基。杂质 C 被确认为 1-[2-[(3-氯苯基)(苯基)甲氧基]乙基]哌啶，是咯培龙的异构体，具有 3-氯取代基。杂质 D 被确认为(4-氯苯基)(苯基)甲酮，是咯培龙合成的原料。杂质 E 被确认为(4-氯苯基)(苯基)甲醇，是咯培龙合成的中间体，也是咯培龙的水解产物。最后，对所建立的方法进行了专属性、线性、灵敏度、精密度和准确度验证。
